2.3.S.2.5. Process Validation and/or Evaluation

Transcription

1 2.3.S.2.5. Process Validation and/or Evaluation 12. What process validation and/or evaluation information is provided, if any? If the validation has been performed, summarized information regarding the validation batches with traceability may be provided, as well as analytical data from the SM, intermediates, IPC s, and final DS. Tabular format is encouraged. Example Table: Validation Batch Information API Lot # Lot A001 Lot A002 Lot A003 Batch Size 100 kg 100 kg 100 kg Starting Material A Lot#/ Input Amount Lot ABC/96 kg Lot DEF/96 kg Lot GHI/96 kg Starting Material B Lot #/ Input Amount Lot RST/50 kg Lot UVX/50 kg Lot YZ/50 kg Intermediate 1 Lot A / %Yield Intermediate 1LotB/ %Yield Intermediate 2 Lot A/ %Yield Intermediate 2 Lot B/ %Yield Lot Lot /87% Lot Lot /87% MNO/87% MNO/87% Lot PQR/82% Lot PQR/82% Lot PQR/82% Lot PQR/82% Lot STU/86% Lot STU/86% Lot STU/86% Lot STU/86% If the validation has not been done, a validation commitment, including the time-line and scale, if applicable, may be provided. *Process validation must be completed before commercial distribution of resulting drug product. (ICH Q11, 1 section 7.1, ICHQ7, "Guidance to Industry. Process Validation: General Principles and Practices.")

2 2.3.S.2.6. Process Development 13. What development and scale up information supports the commercial process and control strategy? Short summary on how the information gained during development is linked to the control strategy, such as attributes controlled by upstream monitoring, intermediate specifications, starting material specifications, process controls and process capabilities. Cite prior knowledge when appropriate Discuss the process design and control strategy Summarize the risk assessment approaches that were used to determine the failure modes. Describe the potential risks or failure modes that affect the CQAs of the drug substance Discuss how the proposed controls mitigate the identified risks in the process. Summarize the development effort on commercial scale process. Summarize how potential scale-up issues have been addressed for scale dependent operations in the synthetic or other processing steps. 2

3 2.3.S.3 Characterization 14. How is the drug substance structure characterized? List of studies that are performed: 1 H-NMR DVS 13 C-NMR pxrd MS UV IR Elemental analysis TGA Specific optical rotation DSC TGA Brief summary of how this data supports the proposed structure 3

4 2.3.S.3 Characterization 15. What are the potential impurities (e.g. related substances, degradants, inorganic impurities, residual solvents) in the drug substance? Which of these impurities are potentially genotoxic? Summarize, in tabular form, observed and potentially present organic impurities (degradants or by-products) with the following information, where appropriate: Structures IUPAC name Proposed acceptance criteria Analytical detection method used (i.e., HPLC with LOD/LOQ, TLC, etc.) Source of the impurity (stage formed in) Type of impurity (i.e., starting material, process impurity, intermediate, degradant, metabolite, and potentially genotoxic impurity (PGI)). 4

5 Example Table: Organic impurities Imp ID Imp A Imp B Compendial Name/IUPAC name USP RC A [IUPAC Name A] Structure Type/Origin Proposed limit and where monitored or controlled [Structure A] Process Imp/Stage II intermediate [IUPAC Name B] [Structure B] Potential degradant Result or Range Analytical Method (LOD/LOQ) 0.30% 0.05% HPLC LOD 0.01% LOQ 0.03% As any unknown 0.10% N/A [IUPAC Name C] [Structure C] Reagent/Stage 2 Eliminated by process* N/A [IUPAC Name D] [Structure D] Reagent/Stage 3 [Additional impurities] (PGI) Theoretical HPLC LOD 0.01% LOQ 0.04% HSGC LOD 1 ppm LOQ 3 ppm *See 3.2.S.2.6, page xxx, for data demonstrating ability of process to eliminate this impurity. Analysis of multiple commercial batches shows this impurity is not detected nd 0.001% % LC/MS LOD 0.5 ppm LOQ 1 ppm 5

6 Example Table: Inorganic impurities Test Origin Acceptance Criteria and where monitored or controlled Pd/C catalyst/ Stage I NMT 10 ppm/in-process step XX Result or Range 3 ppm AA LOD 1 ppm LOQ 3 ppm Analytical Method (LOD/LOQ) Residue on ignition NA NMT 0.10%/release testing Heavy metals NA NMT 20 ppm/release testing 0.02% USP <281> <20 ppm USP <231> Method II 6

7 Example Table: Residual Solvents Name Origin USP <467> Class/Limit Methanol Stage II Class II 3000 ppm Benzene Solvents Class I 2 ppm Acceptance Criteria and where monitored or controlled NMT 3000 ppm/ release testing NMT 50 ppm (in MeOH and Toluene)/control of materials Result or Range Analytical Method (LOD/LOQ) 30 ppm HSGC LOD 10 ppm LOQ 25 ppm 25 ppm* HSGC LOD 1 ppm LOQ 2 ppm *MeOH is not used in final step. See 3.2.S.2., page xxx, for analysis of multiple commercial batches showing benzene is below 2 ppm. 7

8 Example Table: Potential Genotoxic Impurities Imp ID Imp D N/A IUPAC name [IUPAC Name D] [IUPAC Name E] [IUPAC Name C] Structure Alert Aniline Stage Intermediate/Stage 3 Acceptance Criteria and where monitored or controlled NMT 5ppm* /release testing Aniline Reagent/Stage 3 Any unknown impurity limit of 0.10% Primary halide Reagent/Stage 2 Purged below 2 ppm at step 3 Supporting Information Specifications/Analytical method in 3.2.S.4. Ames study negative, report in Annex-III ^ Spike/purge study in 3.2.S.2.6, pp xxx. *Concentration limit (ppm) = 1.5 ug/day divided by the dose in g/day ^Pharmtox data (Ames test, in silico analysis) that is submitted will be sent out for consult 8

9 2.3.S.4 Control of Drug Substance 2.3.S.4.1 Specifications 16. What is the drug substance specification and what is the justification? Does the specification include all of the critical drug substance quality attributes? Information that may be provided includes: A statement that compendial drug substance specifications are compliant with current monograph A table listing each test in the specification, analytical procedure used and acceptance criteria Brief discussion of whether the specification includes all relevant drug substance critical quality attributes 9

10 Example Table: Drug Substance Specification Tests Acceptance criteria Analytical procedure Appearance White solid Visual Identification A B IR spectrum should be concordant with the one of the RS RT of main peak should match the one in RS injection USP <197K> In-house HPLC #1234 Assay % In-house HPLC #1234 Related Substances USP RC A Impurity # 2 Impurity # 3 Impurity RRT 1.2 Any unspecified impurity Total impurities Residual solvents MeOH Toluene NMT 0.20% NMT 0.15% NMT 0.15% NMT 0.10% NMT 0.10% NMT 0.7% NMT 3000 ppm NMT 890 ppm LOD NMT 3.5% (NMT 5.0%)^ KF [additional tests] *USP RC A: IUPAC name *Impurity #2: IUPAC name *Impurity #3: IUPAC name ^ Stability specification in parenthesis In-house HPLC #1235 In-house HSGC #

11 2.3.S.4.2 and 2.3.S.4.3 Analytical Methods and Method Validation 17. For each test in the specification, provide a summary of the analytical procedure(s) and, if applicable, a summary of the validation or verification report(s). A tabular summary of each non-usp method that includes all critical method parameters and system suitability requirements may be provided. A tabular format is preferred. Example Table: Analytical Method Parameters Mobile Phase Acetonitrile: Buffer = 30 : 70 Buffer: Dissolve 6.8 g of KH 2 PO 4 in 1000 ml of water and adjust ph to 7.4 ± 0.05 with triethylamine Column Symtrex C 8, 5 µm, 150 mm 4.6 mm Flow Rate 1.5 ml/minute Temperature 40 C Detector UV at 272 nm Injection Volume 20 µl Run Time 15 minutes Retention Time About 8 minutes Sample Preparation System Suitability Program Standard and sample solutions contain 0.1 mg/ml of MK The column efficiency as determined from the MK peak is NLT 2000 theoretical plates. Tailing factor of the same peak is NMT 2.0. RSD of five replicate injections of standard 1 solution is NMT 2.0% and RSD of the bracketing standard injections (made after every six sample injections) is NMT 2.0%. The % recovery of standard 2 injections relative to the mean of the first five injections of standard 1 is 98.0% %. Gradient or isocratic 11

12 Information that may be provided in 2.3.S.4.3 includes: A tabular summary of the method validation/verification performed for all quantitative instrumental test methods (i.e., assay, impurities, particle size, residual solvents, etc.) that includes the validation parameters evaluated, acceptance criteria, and results. Summary of verification data to show methods adopted from USP are suitable for their use under actual operating conditions. If a USP method is used, it must be validated for in-house impurities Summary of method equivalency data to demonstrate that an inhouse method is equivalent or better than an existing USP method. 12

13 Example Table: Method Validation Parameter Acceptance Criteria Validation Results (Impurities Method) Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F Specificity RT 1.3 min RT 1.7 min RT 5.2 min RT 6.4 min RT 7.0 min RT 13.5 min Linearity/Range R 2 NLT 0.990/range System Precision Method Precision Intermediate Precision %RSD area NMT 10.0%, n= 3 injections of std %RSD w/w NMT 10.0%, n=6 indiv. preparations Cummulative %RSD content NMT 10.0%, n = 12 prep Accuracy Recovery % (3 concentrations, range 50, 100, 120% specification) 0.991,LOQ- 0.15%* 0.995, LOQ- 0.15%* 0.998, LOQ- 0.15%* 0.990, LOQ- 0.15%* 0.993, LOQ- 0.15%* 0.991, LOQ- 0.15%* 2.12% 2.76% 1.53% 4.86% 2.75% 5.21% 3.54% 4.24% 3.43% 2.19% 3.84% 1.76% % % % % % % LOQ* 0.012% 0.008% 0.009% 0.008% 0.010% 0.007% LOD* 0.008% 0.004% 0.004% 0.003% 0.005% 0.003% Solution Stability (Stad and Sample) Robustness *w.r.t. Pass SS, %RSD impurity content NMT 10%, cumulative %RSD impurity content NMT 15% 13

14 2.3.S.4.4 Batch Analysis 18. How do the batch analysis results compare to your proposed specification? Provide a summary of the batch analysis results. Summary of batch analysis data which includes: Batch number, size, manufacturing date. Data from at least three submission batches are preferable. -Quantitative tests must have quantitative data, not conforms or complies Additional data from the batches prepared under certain conditions should be provided and highlighted API manufactured at another site API manufactured using recovered solvents, reagents, intermediate, 2 nd crop drug substance Micronized batches where both micronized and non-micronized are produced Subjected to reprocessing/reworking Batch data may be provided in 2.3.S.4.1 along with specifications with appropriate reference in the response to this question. 14

15 Example Table: Batch Analysis Results Tests Appearance Identification A: B: Assay Residual Solvents Specified Impurities* RC1 RC2 RC3 Any Unspecified Impurity Total Impurities [Additional Specification] Analytical Method *RC 1: [impurity identity] RC 2: [impurity identity] RC 3: [impurity identity] Acceptance Criteria Representative Lot A Representative Lot B Representative Lot C 15

16 2.3.S.4.5 Justification of Specification 19. What is the proposed control strategy for the drug substance manufactured at commercial scale? What are the residual risks upon implementation of the control strategy at commercial scale? Information that may be provided: A summary (tabular form is preferred) of the overall drug substance control strategy which demonstrates understanding of critical quality attributes such as, but not limited to- Assay Organic/inorganic impurities (formation, fate, purge and control) Polymorphic form and particle size Water/solvent content Enantiomeric purity A justification may be provided for tests that were considered, but ultimately not included in the drug substance specification. 16

17 Information that may be provided: If applicable, a brief discussion of residual risk that remains after control strategy is implemented on commercial scale such as: Drug substance CQA s monitored upstream at higher than allowed limit Drug substance CQA s controlled by process parameters without routine monitoring A statement that a firm s quality system will evaluate the manufacturing process to verify the state of control- Periodically After intended or unintended changes occur Where residual risks are considered high or moderate, a specific mitigation plan may be provided 17

18 Example Table: Control Strategy Type of control CQA s from 3.2.S.2.6 Limit in DS Impurity X NMT* 0.15% Impurity Y NMT 0.20% Any individual unspecified impurity NMT 0.10% Total impurities NMT 0.50% Enantiomeric Purity S-Enantiomer NMT 0.50% In Process Controls (Including In- process Testing and Process Parameters) Controls on Material Attributes (Raw Materials/Starting Materials /Intermediates) Design space of the reflux unit operation composed of a combination of %water in Intermediate E and the reflux time in Step 5 that delivers Intermediate F with Hydrolysis Impurity 0.30% (3.2.S.2.2) Process parameters Step 4 (3.2.S.2.2) p(h 2 ) 2 bar, T <50 C IPC Step 4 (3.2.S.2.4) Imp Y 0.50% Spec for starting material D (3.2.S.2.3) Spec for starting material D (3.2.S.2.3) S-enantiomer 0.50% Impact of Manufacturing Process Design Stereocenter is shown not to epimerize (3.2.S.2.6) Is CQA Tested on DS/ Included in DS Specification (3.2.S.4.1) Yes/Yes Yes/Yes Yes/Yes Yes/Yes No/No Residual Solvent Ethanol NMT 5000 ppm Toluene NMT 890 ppm In-process test during drying after final purification step (3.2.S.2.4) LOD 0.40 % In-process test Step 4 (3.2.S.2.4) 2000 ppm by GC In-process results correlated to test results on drug substance (3.2.S.2.6) Process steps after Step 4 are shown to purge toluene to levels significantly below (less than 10%) that indicated No/Yes No/No 1 1 This approach could be acceptable as part of a control strategy when justified by submission of relevant process data that confirms the adequacy of the process design and control. 18

19 2.3.S.5 Reference Standards 20. How are the drug substance reference standards obtained, certified and/or qualified? Information that may be provided for all reference standards associated with the release of a drug substance (may be in tabular form): Lot numbers for compendial drug substance and impurity reference standards For non-compendial reference standards- Origin (purchased, isolated, synthesized), batch/lot number Brief description of the preparation and qualification (characterization and quantification). Data in 3.2.S.3 can be referenced if the same lots are used. If full characterization is not performed, a one time comparison of in-house standards to the corresponding compendial reference standard, where available, may be provided. Reference standard COAs including the storage conditions and expiry date. 19

20 Example Tables: Reference Standards Primary Reference Standards RS ID Compendial Name/IUPAC name Structure Source Characterization Comparison data/reference API API name [Structure API] USP NA NA (lot#) Imp A USP RC A [Structure A] USP RCA NA NA [IUPAC Name A] (Lot#) Imp B [IUPAC Name B] [Structure B] In-house synthesis (lot #) 1 HNMR, 13 CNMR, COSY, HSBC, MS elemental analysis FTIR, UV Data interpretation in 3.2.S.3.2, page xxx COA in 3.2.S.5, page xxx RS ID Secondary (Working) Reference Standards Compendial Name/IUPAC name Structure Source Characterization COA API API name [Structure API] In-house production (Lot#) Imp A USP RC A [IUPAC Name A] [Structure A] In-house synthesis (Lot#) Imp C [IUPAC Name B] [Structure B] Purchased (Lot#) Qualified against primary RS Lot# Qualified against primary RS lot# Qualified against primary RS lot# 3.2.S.5, page xxx 3.2.S.5, page xxx 3.2.S.5, page xxx 20

21 2.3.S.6 Container Closure System 21. What container closure system(s) is proposed for commercial packaging of the drug substance and how is it suitable to ensure the quality of the drug substance during shipping and storage? Information that may be provided: Brief description of the primary and secondary packaging. Reference documentation from each vendor showing compliance for each primary packaging material with 21 CFR ( ) (food safety statement). A summary of how the container closure system protects product quality during shipping and storage (i.e., hygroscopic, light or air sensitive, etc.). Describe how the packaging system used during stability studies is representative of the commercial packaging system. 21

22 Example Table: Container Closure Packing material Description/Function Certifications/CoA Primary Clear LPDE bag/primary protection Compliance with 21CFR S.6, p xxx Specification & CoA 3.2.S.6. p xxx Functional Secondary Black LPDE bag/light protection Specification & CoA 3.2.S.6, p xxx Secondary HDPE drum N/A 22

23 Information that may be provided: A clear, legible copy of the container label which may include, but is not limited to the following: Drug substance name Manufacturer name and address Manufacturing date Gross, net, tare weights Retest date Statements needed to comply with USP requirements Storage conditions (specify numeric temperature which has been supported by stability data) RX and Manufacturing only caution statements Describe any special storage conditions that need to be captured on the label (e.g. protection from light, humidity). 23

24 2.3.S.7 Stability 22. What are the stability acceptance criteria? If applicable, what is the justification for acceptance criteria that differ from the drug substance release specification? Information that may be provided: Stability specification in tabular form similar to the specification presented in 2.3.S.4.1. Brief discussion and justification for any differences in the attributes tested, acceptance criteria, or methods used for release vs. stability (e.g., moisture content, degradants, and solid-state form). Justify tests which are performed at release but removed from stability for non-obvious reasons (i.e., removal of microbiological tests) 24

25 2.3.S.7 Stability 23. What is the proposed retest period for the drug substance? What drug substance stability data support the proposed retest period and storage conditions in the commercial container closure system? How does statistical evaluation of the stability data, if any, and any observed trends support your proposed retest period? Information that may be provided: Retest date and summary of how the stability data supports that retest period. Discussion of the significance and magnitude of any observed trends, and the impact on the proposed retest period and product quality. Refer to ICH Q1E for guidance on statistical evaluation. A summary of the photostability testing studies performed based on ICH Q1B may be provided in this section if applicable. Stability data on 3 batches of a size reflective of the commercial process and of the same quality as the commercial product 25

26 Batch #/Type Test Condition Container Closure System Example Table: Stability Summary Stability Data Trends Yes/No* Batch X1/Pilot Accelerated Black LDPE Bag 0, 3, 6 months. Y, H 2 O content Ranges Observed % Room temperature 0, 3, 6, 9 and 12 months. Y, H 2 O content % Batch X2/Pilot Accelerated Black LDPE Bag 0, 3, 6 months. Room temperature 0, 3, 6, 9 and 12 months. Batch A3/commercial Accelerated Black LDPE Bag 0, 3, 6 months. Y, Imp A % Room temperature 0, 3, 6, 9 and 12 months. Y, Imp A % Batch Y1/ Pilot Accelerated Black LDPE Bag 0, 3, 6 months. Room temperature 0, 3, 6, 9 and 12 months. Batch Y2/ Pilot Accelerated Black LDPE Bag 0, 3, 6 months. Room temperature 0, 3, 6, 9 and 12 months. Batch A1/commercial Accelerated Black LDPE Bag 0, 3, 6 months Room temperature 0, 3, 6, 9 and 12 months. 26

27 2.3.S.7 Stability 24. What are the post-approval stability protocols and other stability commitments for the drug substance? The post-approval stability protocol and commitment should include: Storage conditions of stability samples Samples that will be placed on stability (packaging configuration) Testing intervals Tests to be performed and testing schedule Analytical methods (may refer to 3.2.S.4.2 if the same) The stability commitment should indicate: Validation batches to be placed on stability with commitment to complete the study Commitment to add batches to the stability program on a yearly basis, if manufactured Stability Data: For completeness assessment at least the initial and one time point should be available for each batch Upon being referenced by an ANDA- 6 months accelerated and long-term data should be available for each batch. 27

28 Example Table: Stability Protocol Stability protocol. Test Conditions Test Parameter Test Interval Container Closure System Long-term 25 ± 2 C /60% ± 5 RH As per specifications 0, 3, 6, 12, 18, 24 and 36 months Clear LDPE bag and dessicant pouch placed in Black LDPE. Bags placed in blue HDPE drum. Intermediate* 30 ± 2 C /65% ± 5 RH Accelerated 40 0 ± 2 C/ 75% ± 5% RH As per specification 3,6,9 and 12 months Clear LDPE bag and dessicant pouch placed in Black LDPE. Bags placed in blue HDPE drum. As per specifications 0, 3 and 6 months Clear LDPE bag and dessicant pouch placed in Black LDPE. Bags placed in blue HDPE drum. Example : Testing Schedule a) Description b) Identification by IR* c) Loss on drying (%w/w) d) Assay (by HPLC, %w/w) e) Related substances (by HPLC, %w/w) *The identification by IR test shall be analyzed at 3 and 6 mo in the accelerated stability study, and at 12, 24, 36 and 48 mo in the controlled room temperature stability studies. 28

29 Example Table: Stability Tests/Acceptance Criteria Tests Acceptance criteria Analytical procedure Appearance White solid Visual Identification A IR spectrum should be concordant with the one of the RS USP <197K> Assay % In-house HPLC #1234 Related Substances USP RC A Impurity # 2 Impurity # 3 Impurity RRT 1.2 Any unspecified imp Total impurities Polymorph (by XRD) NMT 0.20% NMT 0.15% NMT 0.15% NMT 0.10% NMT 0.10% NMT 0.7% X-Ray Diffractogram of test is concordant with the XRD of Venlafaxine HCl working standard which is obtained in a similar manner In-house HPLC #1235 In-house HPLC #

30 Thank you for you attention! Any Questions? 30